Role of epigenetics in Type 2 diabetes

By Lai, Cheuk

Epigenetics is the study of the inheritable changes in gene expression without any change to the DNA sequence. (Dupont, Armant & Brenner, 2009) It has been found to drive the development and pathogenesis of Type 2 Diabetes (T2D). T2D is a common disease affecting 422 million people worldwide due to a combination of genetic and environmental factors. The resistance of muscle and adipose cells to insulin and failure of insulin production from pancreatic β‐cells lead to reduced uptake of glucose in the blood, causing hyperglycaemia. (Ling, 2020) Reversible epigenetic modifications such as DNA methylation and acetylation greatly contribute to the inhibition of insulin secretion and impaired insulin responses.

Methylation usually happens when a methyl group is added to the 5th  position of cytosines in CpG sites at the start of the gene to repress gene expression as transcription factors cannot bind. Hypermethylated CpG sites can be bound by methyl-CpG-binding proteins such as histone deacetylase, leading to the formation of heterochromatin and prevention of  transcription. The specific pattern of methylated DNA is maintained in mitosis by DNA methyltransferase-1, by interacting with other DNA binding proteins or RNA interference. (Dupont, Armant & Brenner, 2009) Besides, several miRNAs are also found to be regulating these epigenetic modifications. MicroRNA (miRNA) is short, non-coding RNA that regulates gene expression by repressing translation or degrading mRNA depending on the sequence complementarity. In a diabetic patient, when miR-133a is silenced in cardiomyocytes by injecting anti-miR-133a, expression of DNA methyltransferase-1, -3a and -3b increases, possibly causing hypermethylation of genes associated with diabetic cardiomyopathy. (Chavali, Tyagi & Mishra, 2012)

Environmental factors such as diet quality, physical activities and stress contribute to the induced changes in the epigenome. Volkov et al. compared the DNA methylation pattern in non-diabetic and diabetic human pancreatic islets with whole-genome bisulfite sequencing. They identify 25820 differentially methylated regions (DMRs), which are regions that have different methylation patterns across several types of tissue. 457 genes were found to have a contrasting expression in the pancreatic islets due to differently methylation patterns between non-diabetic and diabetic individuals. An example would be the lower expression level of the SLC2A2 gene that codes for a glucose transporter in pancreatic β‐cells due to hypermethylation in diabetic individuals. In particular, they found out that methylation of the enhancer region in an islet-specific transcription factor, PDX1 can be increased by glucose and a total of 7 DMRs are related to PDX1. This leads to a decrease in PDX1 expression, which can downregulate insulin level in blood and may contribute to the pathogenesis of T2D. (Volov et al., 2017)

Diet quality is a major determinant of the risk of T2D. A recent study by Hall et al. studied the epigenome of the human pancreatic islet after treating the cells with a high concentration of glucose and palmitate. Glucolipotoxic treatment of the cell induces hypermethylation in 2 DNA methyltransferase. Sssl and Hhal will methylate two of the CDK1 methylation sites, 31 and 6 respectively. The decreased expression of CDK1 will affect the functioning and enhance apoptosis of β‐cells function and inhibit the secretion of insulin. The number of genes that were affected by the treatment was 37382 and only 13% of the altered methylation level reverse after the removal of the treatment, suggesting post-diabetic patients with normal blood glucose level may still maintain the majority of altered methylation pattern and only a few methylations will be reversible. (Hall et al., 2019)

As another main risk factor, obesity, contributes to 80-85% of the overall increased risk of developing T2D by altering the genome-wide DNA methylation pattern. (NICE, 2020) The number of DNA methylation is three times higher in an obese muscle cell than a non-obese cell after differentiation. Gene expression changes were observed for a few genes associated with obesity and insulin resistance in obese cells such as L18, PNPLA2 and ENHO. (Davegårdh  et al., 2017) Eighteen genes involved in the adipogenesis pathway are expressed differently in obese women, such as IGF1, NCOR2, RARA. They are upregulated when hypomethylated and downregulated when hypermethylated. (Dahlman et al., 2015) In an epigenome-wide association study, methylation pattern at CpG sites can explain 16.9% of the correlation between obesity and insulin levels, which suggests the pattern can be used to predict the risk of T2D. (Liu et al., 2019) Moreover, methylation at CpG sites of obesity-related genes can regulate target genes that will affect how easy is weight gains and losses. In leukocytes, Methylation at the CpG dinucleotides within the promoters of NPY and POMC genes can influence how well an obese individual can maintain its weight after a diet. NPY proteins play an important role in lipogenesis, adipogenesis and determining the insulin sensitivity, regulated by a sterol regulatory element binding protein (SREBP) that can bind to CpG3 and as well as an enhancer-binding protein at CpG8_9_19. Helping to maintain body weight homeostasis, POMC protein is regulated by the binding of insulator protein that has a conserved zinc-finger motif at CpG10_11. Individuals have hypermethylation at POMC CpG10_11, hypomethylation at NPY CpG3 and CpG8_9_19 will be more likely to regain the lost weight after their diets. (Crujeiras et al., 2013) 

In conclusion, induced changes in the epigenome by environmental factors shapes the methylation landscape of an individual, determining the risk of developing T2D. Methylation patterns can be useful in creating blood-based biomarkers to identify high-risk individuals for early identification and prevention of T2D. (Ling, 2020) Further understanding of the underlying epigenetic mechanisms to regulate diabetes-related genes are definitely crucial to improve existing therapies.

References:

Chavali, V., Tyagi, S. C., & Mishra, P. K. (2012). MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes. Biochemical and biophysical research communications425(3), 668–672. Available from: https://doi.org/10.1016/j.bbrc.2012.07.105 [Accessed 29/11/2020]

Crujeiras, A. B., Campion, J., Díaz-Lagares, A., Milagro, F. I., Goyenechea, E., Abete, I., Casanueva, F. F. & Martínez, J. A. (2013) Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: A translational study. Regulatory Peptides. 186 1-6. Available from: https://doi.org/10.1016/j.regpep.2013.06.012. [Accessed 29/11/2020]

Dahlman, I., Sinha, I., Gao, H. et al. (2015) The fat cell epigenetic signature in post-obese women is characterized by global hypomethylation and differential DNA methylation of adipogenesis genes. Int J Obes 39, 910–919. Available from: https://doi.org/10.1038/ijo.2015.31 [Accessed 29/11/2020]

Davegårdh, C., Broholm, C., Perfilyev, A. et al. Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects. BMC Med 15, 39 (2017). https://doi.org/10.1186/s12916-017-0792-x [Accessed 29/11/2020]

Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: definition, mechanisms and clinical perspective. Seminars in reproductive medicine27(5), 351–357. Available from:  https://doi.org/10.1055/s-0029-1237423 [Accessed 29/11/2020]

Hall, E., Jönsson, J., Ofori, J. K., Volkov, P., Perfilyev, A., Dekker Nitert, M., Eliasson, L., Ling, C., & Bacos, K. (2019). Glucolipotoxicity Alters Insulin Secretion via Epigenetic Changes in Human Islets. Diabetes68(10), 1965–1974. Available from: https://doi.org/10.2337/db18-0900 [Accessed 29/11/2020]

Ling, C (2020). Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes (Review). J Intern Med 2020; 288: 158– 167. Available from: https://doi.org/10.1111/joim.13049 [Accessed 29/11/2020]

Liu, J., Carnero-Montoro, E., van Dongen, J., Lent, S., Nedeljkovic, I., Ligthart, S., Tsai, P. C., Martin, T. C., Mandaviya, P. R., Jansen, R., Peters, M. J., Duijts, L., Jaddoe, V., Tiemeier, H., Felix, J. F., Willemsen, G., de Geus, E., Chu, A. Y., Levy, D., Hwang, S. J., … van Duijn, C. M. (2019). An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis. Nature communications10(1), 2581. Available from: https://doi.org/10.1038/s41467-019-10487-4 [Accessed 29/11/2020]

NICE. (2020) Diabetes – type 2:
What are the risk factors? Available from: https://cks.nice.org.uk/topics/diabetes-type-2/background-information/risk-factors/ [Accessed 29/11/2020]

Volkov, P., Bacos, K., Ofori, J. K., Esguerra, J. L., Eliasson, L., Rönn, T., & Ling, C. (2017). Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis. Diabetes66(4), 1074–1085. Available from: https://doi.org/10.2337/db16-0996 [Accessed 29/11/2020]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s